Schiff bases of 4-amino-2,2,5,5-tetrakis (fluoroalkyl)-3-imidazolines



s 536 104 SCHIFF BASES F l-A1\/1IN0-2,2,5,5-TETRAKIS (FLUOROALKYL)-3-IMIDAZOLINES I David M. Gale, Wilmington, DeL, assignor to E. I. du

Pont de Nemours and Company, Wilmington, Del., a corporation of Delaware No Drawing. Filed Aug. 10, 1966, Ser. No. 571,396

. Int. Cl. C07d US. Cl. 260-240 4 Claims ABSTRACT OF THE DISCLOSURE (l) Schilf bases of 4-amino 2,2,5,5 tetrakis (fluoroalkyl-3-imidazolines and 4-amino-2,2,5,5-tetrakis(fluoroalkyl)-3-oxazolines of the formula I wherein Z, Z Z and Z which may be the same or different, are selected from hydrogen, chlorine and fluorine; R is hydrogen or a monovalent radical containing at most 18 carbons selected from alkoxy, dialkylamino, dialkylaminoaryl and alkoxyaryl; and R is selected from R and a monovalent radical containing at most 18 carbons selected from alkyl, aryl, alkaryl and aralkyl; and X is selected from O and NH, aryl being a carbocyclic radical selected from phenyl and naphthyl;

(2) A process for preparing said Schiif bases by reaction of an isocyanate with a carbonyl or thiocarbonylcontaining compound; and

(3) Pharmaceutical compositions containing a beneficial amount of the aforesaid Schilf bases.

The compounds of this invention are useful in lowering the formation temperature or pressure of polymers, as dyes and as muscle relaxants.

FIELD OF THE INVENTION This invention relates to Schifi bases of fluoroalkyl substituted aminoheterocyclics, to a process for their preparation, to pharmaceutical compositions containing a beneficial amount of these Schitf bases and to a process for administering, to a warm-blooded animal, the pharmaceutical compositions to produce a physiological effect.

DETAILS OF THE INVENTION This invention is directed to Schiif bases of 4-amino- 2,2,5,5-tetrakis(fluoroalkyl)-3-imidazolines and 4-amino- 2,2,5,5-tetrakis(fluoroalkyl)-3-oxazolines of the formula and to a process for producing these Schifi bases. In

Formula I, Z, Z Z and Z can be the same or different and are selected from hydrogen, chlorine and fluorine; R is hydrogen or a monovalent radical containing at most 18 carbons selected from alkoxy, dralkylammo, dialkyl- United States Patent 0" 3,536,704 Patented Oct. 27, 1970 ZOF:

wherein X, Z, Z Z and Z are as defined above with a carbonyl or thiocarbonyl-containing compound of the formula wherein Y is selected from oxygen and sulfur and R and R are as defined above.

The process for preparing the Schifi bases of this invention is conducted at a temperature of about 20-250 C. using essentially anhydrous conditions and preferably an inert atmosphere such as nitrogen. Preferably, the reaction is conducted at a temperature of about 220 C. Moderate reaction temperatures such as 70-160 C. are also used, especially when the carbonyl or thiocarbonyl reactant is a good reducing agent.

Solvents or diluents which are inert to the reactants and products such as ethers, for example the dimethyl ether of diethylene glycol, or dioxane, or other inert solvents such as chlorobenzene, methylene chloride, tetrachloroethylene, xylene and the like can be used in the process for producing the Schitf bases. The process also can be conducted with excess carbonyl or thiocarbonyl-containing compound as the reaction solvent. A mole ratio of the heterocyclic isocyanate to carbonyl or thiocarbonylcontaining compound of about l.0:2.0 is preferred. The reaction can be conducted using a mole ratio of reactants of about 0.5: 10 or higher.

The products of this invention can be isolated from the reaction mixture by distillation, vacuum sublimation or crystallization.

Schilf bases (I) possess pharmacological activity which is therapeutically useful in the treatment of neurological and psychiatric disorders in warm-blooded animals. The Schilf bases exert depressant effects upon the central nervous system, resulting in a decrease in skeletal muscle tone. This depressant elfect is a desirable property for the treatment of hypertonic and hyperkinetic motor disorders. The depressant effect is also useful for producing relaxation during administration of a general anesthesia.

An embodiment of this invention is a pharmaceutical composition containing a physiologically beneficial amount of a Schiff base of Formula I as the active ingredient and a nontoxic pharmaceutical carrier.

The active ingredient of this invention can be employed in useful compositions according to the present invention in such dosage forms as tablets, capsules, powder packets, or liquid solutions, suspensions, or elixirs, for oral administration or liquid solutions for parenteral use," and in certain cases, suspensions for parenteral use (except intravenous). In such compositions the active ingredient will ordinarily always be present in an amount of at least 0.02% by weight based on the total weight of the composition and not more than 99% by weight.

The pharmaceutical carrier can be a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil and the like. In general, water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers. Suitable pharmaceutical carriers are described in Remingtons Practice of Pharmacy by E. W. Martin and E. F. Cook, a well-known reference test in this field.

The dosage administered will be dependent upon age, health and weight of the recipient, the kind of concurrent treatment if any, frequency of treatment, and the nature of the effect desired. Generally, a daily dosage of active ingredient compound will be from about 0.05 to 50 mg. per kg. of body weight, although lower, such as 0.01 mg./ kg., or higher amounts can be used. Ordinarily, from 0.1 to 20 and preferably 0.1 to mg./kg. per day, in one or more applications per day, is effective to obtain the desired result.

A process embodiment of this invention comprises administering to a warm-blooded living animal a physiologically beneficial amount of a Schiff base of Formula I or a physiologically beneficial amount of a pharmaceutical composition containing a Schiff base of Formula I and a nontoxic pharmaceutical carrier. The Schiff base can be administered orally and parenterally.

The isocyanates of Formula II are prepared by a series of reactions involving either a fluoroketone or a fluoroketimine which are converted to 4-amino-2,2,5,5-tetrakis (fiuoroalkyl) 3 oxazolines and 4-amino-2,2,5,5-tetrakis (fiuoroalkyl)-3-imidazolines (or their tautomers-4-imino- 2,2,5,5'- tetrakis(fluoroalkyl)oxazolines and 4 imino- 2,2,5,5 tetrakis (fluoroalkyl)imidazolidines, respectively) which are subsequently converted into 4-isocyanato- 2,2,5,5 tetrakis(fluoroalkyl) 3 oxazolines and 4-isocyanato-2,2,5,5-tetrakis(fluoroalkyl)-3-imidazolines.

4-isocyanato-2,2,S,5 tetrakis(fluoroalkyl)-3-oxazolines, the compounds of Formula II in which X is oxygen, are used as a starting material for producing some Schiif bases of this invention. These compounds are prepared by the reaction of a fluoroketone of the formula in which Z and Z are as defined above with an alkali metal cyanide in a polar solvent to produce the alkali metal salt of the fluoroketone cyanohydrin which is then reacted with a fluoroketimine of the formula in which Z and Z are as defined above. Acidification of the resulting reaction mixture followed by purification yields the 3-oxazoline. This process is described in further detail in Example A and in U.S. Pat. 3,442,904.

4 amino-2,2,5,5-tetrakis(fluoroalkyl)-3-imidazolines, used for preparing the imidazoline isocyanates of Formula II in which X is NH, are prepared by reacting three moles of a ketimine of Formula V with 1 mole of an alkali metal cyanide, followed by heating the reaction mixture with acid such as concentrated sulfuric acid. Imidazoline intermediates having different Z groups on the 2 and 5 position can be produced from a mixture of fluoroketimines. This latter process produces a mixture of imidazolines. Preparation of 4-amino-2,2,5,5-tetrakis (fluoroalkyl)-3-imidazolines is described in greater detail in Examples B and C and in U.S. Pat. 3,459,766.

4 isocyanato-2,2,5,5-tetrakis(fiuoroalkyl)-3-oxazolines and 4 isocyanato-Z,2,5,5-tetrakis (fluoroalkyl)-3-imidazolines are prepared by the reaction of the corresponding 4 amino heterocyclic compounds with a phosgenating agent such as oxalyl chloride. The phosgenation reaction is accomplished without solvent or in an inert solvent at ambient or slightly elevated temperatures. Preferably, a mole to mole ratio of the amino-heterocyclic compound and oxalyl chloride is used. The reaction is conducted under essentially anhydrous conditions. The phosgenation process, which is applicable to the imidazolines and oxazolines, is described in Examples D and E and in U.S. Pat. 3,410,866.

The fiuoroketimines of Formula V used in the abovedescribed process are prepared in various ways. Imines wherein Z, Z Z and Z are fluorine or chlorine can be prepared as shown in U.S. Pat. 3,226,439 and in W. J. Middleton and C. G. Krespan, J. Org. Chem., 30, 1398 (1965). Fluoroketimines where Z, Z Z and Z are hydrogen can be prepared by a modification of the method for preparing hexafluoroisopropylidenimine, Zeifman et al., Akad. nauk. S,S.S.-R. Doklady, 153, 1334 (1963). This process consists of reacting pentafluoroacetone with phenyl isocyanate at about 200 C. in the presence of a catalytic amount of a triarylphosphine oxide followed by the reaction with ammonia which results in N-phenyl-2,2- diaminopentafluoropropane. This product, which is not necessarily isolated, is heated with phosphorus pentoxide with the formation of the fluoroketimine, pentafluoroisopropylidenimine. This process is described in greater detail in Example E and in U.S. Pat. 3,342,864.

The fiuoroketones IV are Well-known materials and have been described in Lovelace, Rausch and Postelnek, Aliphatic Fluorine Compounds, Reinhold Publishing Corporation, New York (1958), pp. -192.

Carbonyl and thiocarbonyl-containing compounds used as the coreactant are well-known compounds, many of which are commercially available.

Carbonyl and thiocarbonyl-containing compounds useful in the process for preparing the compounds of Formula I include:

acetaldehyde thioacetaldehyde propanal thiopropanal b utanal dodecanal thiododecanal octadecanal thiododecanal fi-naphthaldehyde a-thionaphthaldehyde phenylacetaldehyde o-tolualdehyde u-phenylpropionaldehyde 2,3,5,G-tetramethylbenzaldehyde 2,4,6-triethylbenzaldehyde p-n-propylbenzaldehyde thiophenylacetaldehyde p-thiotolualdehyde p-dimethylaminobenzaldehyde p-methoxybenzaldehyde p-ethoxybenzaldehyde p-methoxythiobenzaldehyde 4-methoxy-1-naphthaldehyde 4-dimethylamino-l-naphthaldehyde methyl N,N-dimethylcarbamate ethyl N,N-diethylcarbamate octadecyl N,N-dimethylcarbamate ethyl N,N-dibutylcar-bamate 4,4-dimethoxybenzophenone ethyl-p-methoxyphenyl thioketone hexyl-p-methoxyphenyl ketone decyl-4-methoxyphenyl ketone rnethyl-1-(4-methoxy) naphthyl ketone methyl-l (4-hexoxy) naphthyl ketone 4-methoxy thiobenzophenone 4-dimethylaminobenzophenone 4-methoxy-4-dimethylaminobenzophenone 4,4-bis(dimethylamino)benzophenone 1-(4-methoxy)naphthylmethyl ketone naphthyl-p-methoxyphenyl ketone 4,4'-dimethylaminophenyl thioketone methyl formate dodecyl formate heptadecyl formate methyl acetate methyl thioacetate butyl thioacetate butyl acetate 1 dodecyl acetate I dodecyl butyrate hexadecyl acetate dodecyl hexanoate methyl benzoate ethyl thiobenzoate butyl benzoate octyl benzoate decyl benzoate undecyl benzoate a-napthyl a-naphthoate hexadecyl N,N-dimethylcarbamate hexadecyl 4-dimethylamino-1-naphthoate 4-dimethylaminonaphthyl butyrate a-naphthyl benzoate benzyl benzoate p-methylphenyl benzoate benzyl phenylacetate methyl p-dimethylaminobenzoate methyl m-diethylaminobenzoate N,N-dimethylbenzamide N,N-dimethylphenylacetamide N,N-dimethyl-p-dimethylaminophenylacetamide N,N-dimethyl-p-methoxyphenylacetamide N,N-dimethylthiobenzamide N,N-dimethylthiophenylacetamide and the like. Other carbonyl and thiocarbonyl-containing compounds are shown below in the examples.

EMBODIMENTS OF THE INVENTION The following examples further illustrate the invention. Unless otherwise specified, temperatures and pressures in these examples were ambient. Tautomeric forms of the imidazoline compounds are sometimes omitted from structural formulas. Examples A-F illustrate the preparation of the isocyanato intermediates for the Schifi Hexafluoroacetone, 25 ml. at -78 C. (ca. 0.25 mole), was slowly distilled over a period of 30 min. into a stirred suspension of 12.25 g. (0.25 mole) of powdered sodium cyanide in 200 ml. of acetonitrile. The temperature of the reaction rose spontaneously to C. The reaction mixture was stirred for an additional 30 min., and then cooled to 25 C. Hexafluorosiopropylidenimine, 27 ml. at '-10 C. (ca. 0.25 mole), was then distilled into the reaction mixture, and the mixture was stirred for 3 days at room temperature. An equal volume of water was added, and the mixture was neutralized with 10% aqueous hydrochloric acid. The organic layer that formed was separated and shaken with water until a solid formed. The solid was collected on a filter, washed with water, recrystallized from benzene, and then submitted at C. and 10 mm. to give 33.0 g. (37% yield) of 4-amino-2,2, 5,5-tetrakis(trifluoromethyl) 3 oxazoline as colorless crystals, M.P. 136l38 C. (sealed capillary). The infrared spectrum showed a band at 5.8914. The H N.M.R. spectrum in (CD CO at 25 C. showed a broad singlet at 7.66 p.p.m., and at 50 showed two singlets of equal area at 8.00 and 7.75 p.p.m. lower field from (CH Si. The F N.M.R. spectrum in (CD SO showed two septets (J'=5.9 c.p.s.) centered at 72.0 and 77.1 p.p.m. higher field from trichlorofluoromethane.

Analysis.-Calcd. for C H F N O (percent): C, 23.47; H, 0.56; F, 63.67; N, 7.83. Found (percent): C, 23.88; H, 0.77; F, 64.11; N, 7.89.

Perfluoroisopropylidenimine and substituted fluoroisopropylidenimines can be prepared by the procedure described in Example III of US. Pat. 3,226,439.

Among the 4 amino-2,2,5,5-tetrakis(fluoroalkyl) 3- oxazolines which can be prepared by the procedure of Example A are those listed in Table I. The reactants are listed in the left-hand columns of the table and the prodbases of this invention. 50 uct is listed in the right-hand column.

TABLE I Reactants Product oxazolines Ketone Cyanide Imme (or tautomer) 0 NH NH, II It 0 F eu o-0E3 KCN CICF CF Cl 3 N CF3 l O---CF:C1

0 INH N Hg olcrr-t i-omol NaON om-d-or. 01oF" OlCFa O CF3 CFz O IIVH N Hz ctcri-i i-crs NaON OF -(i-OIMH CF3 N ClCFa l i CFQ TABLE I-Oontinued Reactants Product oxazolines Ketoue Cyanide Imine (or tautomer) llvH NH; C1OF;( 1CF Cl KON oiol r-o-omoi 01oF N CICF: I

CFzCl I) c I'VE NHz Horn-(Lorin NaON HCFfl-CF2H HCFZ HCF: I

o oF,H

GFQH

IFTH I NH: Homeomm NaON oFaccF 91oF" N HCFa I Fa I I NH: Grader; NaCN oraoomol on N CF: I I

CFECI l n I oraoonu NaCN om-d-cm CFS HCF:

O-CF3 F s o IlqH NH, Hom-d-om NaCN Hon-d-om N HQ 2 I O-(-CFa FQH O IIVH NH: or -i i-om NaCN HCFz--GFz N CF: I

- CFa 0 IITH NH: HCF -QL-GFzli NaCN om-d-on N HCF: V O- 0E3 EXAMPLE B 4-(2-amino'- 1,1.,1,3,3,3 hexafluoropropylamino)-2,2,5, I H01 5 tetrak1s(tr1flu0romethy1) 3 lmldazohne and its HNC(OF:)2NH2 NC(CFa)2NHz tautomer 9 9 OF: 0 CF: 0 Na NC(CF3)2NH: /f F 7 F CF 0 C 3 on HN-COF: 0F; HNOCFa NaON C=NH 0 N I u or: F1 Part A.Hexafiuoroisopropylidenimine, 20 ml. at

10 C. (ca. 30.8 g., 0.187 mole), was slowly distilled into a stirred suspension of 3.06 g. (0.0625 mole) of powdered sodium cyanide in 50 ml. of dimethyl sulfoxide.

W An exothermic reaction ensued. The rate of addition of CFa C the ketimine was adjusted so that the temperature of the 6 e; reaction mixture did not rise above 65 C. At the end of L H01 CF:

the addition, about 20 minutes being required, the reaction mixture became homogeneous. The mixture was cooled to 20 C. and then poured into 500 m1. of water containing 100 ml. of 10% hydrochloric acid. The oil that formed was separated by decanting the aqueous phase. Fresh water (500 ml.) was added, and the oil and water were shaken vigorously together. The oil solidified. This solid was collected on a filter and pressed dry, and then dried in a vacuum desiccator over phosphorus pentoxide. There was obtained 24.1 g. (74% of theory) of 4[2- amino 1,1,1,3,3,3-hexafluoropropylamino]-2,2,5,5-tetrakis(trifluoromethyl) 3 imidazoline as a hydrophobic white solid, M.P. 45-46 C. A sample was recrystallized from pentane for analysis. The F N.M.R. spectrum in amino 1,1,1,3,3,3 hexafluoropropylamino]-2,2,5,5-tetra- CD01 showed two septets (i= .0 c.p.s.) centered at 72.8 and 77.9 p.p.m. from .trichlorofluoromethane used as an internal standard and a singlet at 79.8 p.p.m. all of equal area. The proton N.M.R. spectrum in CDCl showed two very broad singlets at 5.55 and 3.57 p.p.m. (each, area 1) and a borad singlet at 3.08 p.p.m. (area 2) from tetramethylsilane used as an internal standard. The infrared spectrum showed a band at 5.971s.

Analysis.--Calcd. for C H F N (percent): C, 23.00; H, 0.77; F, 65.49. Found (percent): C, 23.21; H, 0.91; F, 65.23.

Parts B.-4-amino 2,2,5,5 tetrakis(trifluoromethyl)- 3-imidazoline and its tautomer.

HNC (C FahNHz NH:

4 [2 amino 1,1,1,3,3,3 hexafluoropropylamino]- 2,2,5,5 tetrakis(trifluoromethyl) 3 imidazoline, 47.1 g., prepared as described in Part A above, was dissolved in 100 ml. of concentrated sulfuric acid, and the stirred solution was heated slowly to 150 C. and held at that temperature for minutes. Frothing occurred during the heating period. The solution was then cooled to 20 C. and poured over 1 liter of crushed ice. The White solid that formed was collected on a filter after the ice had melted, and was washed with water. Recrystallization from alcohol-water (1:2) gave 31.5 g. (98% yield) of 4-amino 2,2,5,5 tetrakis(trifluoromethyl)-3-imidazoline or its tautomer as long, colorless needles, M.P. 158*- 159 C.

EXAMPLE C 4-amino-2,2,5,5-tetrakis (trifluoromethyl)-3-imidazoline or its tautomer slowly distilled into a stirred suspension of 10 g. (0.2

mole) of sodium cyanide in 50 ml. of acetonitrile. An exothermic reaction ensued. The mixture was cooled to keep the temperature below 35 C. After the addition, the reaction mixture was stirred for 30 minutes at room temperature, and then 50 ml. of water was added. The pH of the solution was adjusted to 7 by the addition of a small quantity of hydrochloric acid. The organic layer was separated, washed twice with water and dried with anhydrous magnesium sulfate. The liquid was removed by distillation at atmospheric pressure, and the solid residue was recrystallized twice from benzene using decolorizing charcoal. There was obtained 4.1 g. of theory) of 4-amino 2,2,5,5 tetrakis(trifluoromethyl) 3 imidazoline as colorless needles, M.P. 159-160 C. The proton N.M.R. spectrum in dimethyl sulfoxide contained a broad singlet at +7.2 p.p.m. (area 2) and a sharp singlet at +6.06 p.p.m. (area 1). The F N.M.R. spectrum in acetone contained a pair of septets (J=4.7 c.p.s.) at 71.5

and 76.5 p.p.m. from trichlorofluoromethane used as an internal standard. The infrared spectrum contained bands at 2.85, 2.9, 2.96, 3.04, 3.10, 3.16, 5.9 and 6.2;. The very strong band at 5.9 1. indicates the 4-imino tautomer to be present in major amount.

Analysis.--Calcd. for C HF N (percent): C, 23.55; H, 0.85; F, 63.85; N, 1.77. Found (percent): C, 23.77; H, 1.35; F, 64.05; N, 12.05. 7

Among the 4-amino 2,2,5,5 tetrakis(flu0roalkyl)- 3-imidazolines which can be prepared by the procedures of Example B or C are those listed in Table H. The reactant ketimines are listed in the left-hand column and the products are listed in the right-hand column.

TABLE II Product imidazolines (or Reactant ketimmes tautomer) lfiIH NHz 0123-0-01201 019 F2 A HN-c F2 lfiIH NH: 010 F2C-C F201 010 F2 N 010 F2 I HN--l'C F201 IFTH N112 CFa-C-CFzH CF23 HN-O F211 lfil'H lfiIH NHz CF OCF +OFzC1CC F201 Clam HN---'C Fa EXAMPLE D 4-isocyanato-2,2,5,5-tetrakis(trifluoromethyl) -3- imidazoline NH: 1110 o (0 F920 N 01000001 (CFa)zC N HN- -C (0 Fa): HNC(CFs):

or tautomer.

A three-necked flask attached to the bottom of a spinning-band fractionating column was equipped with a magnetic stirrer, nitrogen inlet and dropping funnel. The equipment was flame-dried and cooled; then 15 ml. of oxalyl chloride and 75 ml. of anhydrous diethyl ether were introduced into the flask at ambient temperature under positive nitrogen pressure. To this a solution of 30 g. of 4 amino 2,2,5,5 tetrakis(trifluoromethyl)-3-imidazoline (or its tautomer) dissolved in ml. of ether was added over 30 minutes with vigorous stirring. After stirring an additional 20 minutes, the ether was removed by distillation at a moderate rate and the residue distilled at 75 mm. The product, 4 isocyanato 2,2,5,5 tetrakis- (trifluoromethyl)-3-imidazoline, B.P. 78 C. (75 mm.), 25.7 g., was collected in oven-dried vails (as it reacts with moist air). The H N.M.R. spectrum showed a singlet (broad) at 3.6 p.p.m. The F N.M.R. spectrum showed a pair of septets (J=5) at +73.3 and +78.0 p.p.m. from external FCCl at 56.4 mc.

Analysis.Calcd. for C HN OF (383.12) (percent): C, 25.08; H, 0.26; N, 10.96. Found (percent): C, 25.58; H, 0.77; N, 11.51.

EXAMPLE E 4-Is0cyanato-2- difluoromethyl) -2,5 ,5 -tris(trifluoromethyl) -3 -oxazoline A solution of 15 g. of 4-amino-2-(difiuoromethyl)-2,5, 5-tris(trifiuoromethyl)-3-oxazoline in 50 ml. of oxalyl chloride was heated at reflux for 2 days, and then distilled. There was obtained 11.21 g. of 4-isocyanato-2- (difluoromethyl)-2,5,5-tris(trifluoromethyl) 3 oxazoline as a colorless liquid. B.P. 6567 C. (mostly 67 C.) (50 mm.). The H N.M.R. spectrum of a heat sample showed a triplet (1:53 c.p.s.) split further to a quartet (J=0.9 c.p.s.) centered at 1- 4.26. The F N.M.R. spectrum showed multiplets centered at 4166 c.p.s. (6F), 4406 c.p.s. (3F), and 7600 c.p.s. (2F) from CFCL used as an external standard.

Analysis.-Calcd. for C HF N O (percent): C, 26.25; H, 0.28; F, 57.09; N, 7.65. Found (percent): C, 26.51; H, 0.61; F, 57.02; N, 7.33.

EXAMPLE F Pentafluoroisopropylidenimine Part A.A mixture of 71.4 g. (0.6 mole) of phenyl isocyanate, 92 g. (0.62 mole) of pentafluoroacetone and g. of triphenylphosphine oxide was heated at 200 C. for 16 hours in a 400-ml. bomb. The bomb was cooled and vented, and the contents were distilled to give 75.6 g. (56% yield) of N-phenylpentafluoroisopropylidenimine as a light yellow oil, B.P. 59.6-60 C. (10 mm.), r2 1.4394.

Part B.Ammonia, 21 ml. at 78 C. (ca. 1 mole) was slowly distilled into 74.3 g. (0.33 mole) of N-phenylpentafluoroisopropylidenimine contained in a flask cooled by an ice bath and connected to a Dry Ice-cooled condenser. The reaction mixture was allowed to reflux for 2 hours, and then stirred at room temperature overnight. The entire reaction mixture, ca. 60 ml., was mixed with 200 g. of phosphorus pentoxide contained in a flask connected to a simple distillation column. The flask was heated strongly to distill out the volatile products. The distillate was redistilled to give 26.1 g. (52% yield) of pentafluoroisopropylidenimine as a colorless liquid, B.P. 42.5 C., n 1.3.

EXAMPLE I 4- (dimethylamino) methylmethyleneamino] -2,2,5,5- tetrakis (trifluoromethyl) -3-imidazoline NCO OF; G 0 CH3 C N CFa+CHaCN l/ OF: HN-C OF:

CFs

/CH3 =C\ /OH:

O N CFa CH3 A 7-g. sample (0.02 mole) of 4-isocyanato-2,2,5,5- tetrakis(trifiuoromethyl)-3-imidazoline (as its self-condensation product obtained by storing the isocyanate several days at 25 C. in a closed container) and 10 ml. (excess) of dry dimethylacetamide were heated at reflux under nitrogen for 16 hours. The excess dimethylacetamide was removed by distillation at 5 mm. The residue was short path-distilled giving 5.48 g. B.P. C. (2 mm.) to 77 C. (0.2 mm.), M.P. 45- 51 C. (heart fraction M.P. 48-51 C.) of 4-[(dimethylamino)methylmethyleneamino] 2,2,5,5 tetrakis(trifluoromethyl)-3-imidazoline. The H N.M.R. spectrum showed absorptions: NH at 1- 4.28,

--N(CHs)z :fiamm at T 6.75 and 6.82, and

at 'r 7.60. The F N.M.R. spectrum showed a pair of septets (J=4 c.p.s.) at +41l2.5 and +4391 c.p.s. from external FCCl at 56.4 me. The ultraviolet spectrum showed 3323? at 276 m (e=21,300)

and the mass spectrum showed a parent ion at m/e 426 and the expected fragments.

Analysis.Calcd. for C H N F (426.22) (percent): C, 30.67; H, 2.36; N, 13.14. Found (percent): C, 30.83; H, 2.55; N, 12.95.

EXAMPLE II 4- (dimethylamino) methyleneamino] 2,2,5 ,5 -tetrakis- (trifluoromethyl) -3 -imidazoline A 7-g. (0.02 mole) sample of 4-isocyanato-2,2,5,5- tetrakis(trifiuoromethyl) 3 imidazoline (as its selfcondensation polymer) and 10 g. (excess) of dry diethylformamide were heated together under a nitrogen atmosphere at C. for one hour. The excess diethylformamide was removed under reduced pressure and the residue vacuum sublimed. A total of 4.3 g. (49%) of 4-[(diethylamino)methyleneamino] 2,2,5,5 tetrakis (trifluoromethyl) 3 imidazoline, M.P. 59-63 C., was obtained. The H N.M.R. spectrum showed absorptions: methylene as two overlapping quartets (Js=7 c.p.s.) at at 1- 6.38 and methyls at 1- 8.69 (triplet, 1:7 c.p.s.) and 1 8.80 (triplet, J :7 c.p.s.) due to the presence of NH bands appeared at -r 1.4 and 4.3. The F N.M.R. spectrum showed a pair of septets (J=4.5 c.p.s.) at +4118 and +4394 c.p.s. from external FCCl at 46.4 mc.

Analysis.Calcd. for C H N F (440.25) (percent): C, 32.73; H, 2.75; N, 12.73; F, 51.79. Found (percent): C, 32.59; H, 2.98; N, 12.60; F, 51.36.

EXAMPLE In 4 [p-(dimethylamino)phenylmethyleneamino] 2,2,5,5- tetrakis (trifluoromethyl) -3-imidazoline NCO :trum showed a singlet at -r 1.03 for =CH, an aromatic AA'BB pattern with halves centered at 1- 2.05 and 3.15, NH at 'r 3.70 and N(CH at 1- 6.86. The F N.M.R. spectrum showed a pair of septets (J= c.p.s.) at +4098 and +4367 c.p.s. from external FCCl at 56.4 mc.

Analysis.Calcd. for C H N F (488.29) (percent) C, 39.35; H, 2.46; N, 11.48; F, 46.69". Found (percent): C, 39.69; H, 2.91; N, 11.71; F, 46.84.

EXAMPLE IV 4 [bis(p dimethylaminophenyl)methyleneamino]- 2,2,5,5-tetrakis(trifluoromethyl)-3-imidazo1ine OFa A 7.66-g. (0.020 mole) sample of 4-isocyanato-2,2,5,5-

"tetrakis(trifluoromethyl)-3-imidazoline (as its self-condensation polymer) and 5.68 g. (0.020 mole) of 4,4'-bis (dimethylamino)thiobenzophenoue and ml. of dry dimethyl ether of diethylene glycol (diglyme) were heated at reflux for one hour under nitrogen. Removal of the solvent by distillation and vacuum sublimation of the residue led to 9.2 g. (77%) of red, solid 4-[bis(p-dimethylaminophenyl)methyleneamino] 2,2,5 ,S-tetrakis- '(trifiuoromethyl)-3-imidazoline, M.P. 188-192" C. The

H N.M.R. spectrum showed an aromatic A B pattern with halves at -r 2.44'and 3.30 (area 4:4), NH at 1- 3.95

(area 1) and N(CH at 1- 6.98 (area 12). The F N.M.R. spectrum showed a pair of septets (J=45 c.p.s.)

at +4070 and +4351 c.p.s. from external FCCI at 56.4 me.

Analysis.-Calcd. for C H N F (607.45) (percent): C, 47.45; H, 3.49; N, 11.54; F, 37.5. Found (per-- cent): C, 47.56; H, 3.34; N, 11.57; F, 37.55.

EXAMPLE V 4- ethoxy) phenylmethylene amino] -2,2,5 ,5 tetrakis (trifluoromethyl) -3 -imidazoline NC 0 G F 3 C\ C F: HN-(|3 CFa C F a II coi -0001120133 l CFa C OCH2CH3 A 5-g. sample of 4-isocyanato-2,2,5,S-tetrakis(trifluoromethyl)-3-imidazoline solid condensation product was refluxed (212 C.) with 20 g. (excess) of ethyl benzoate for 3 days. The excess diethyl benzoate was removed by distillation and the residue distilled through a spinningband column. The fractions boiling at C. (0.3 mm.) to 78 C. (0.25 mm.), 1.7 g. (26%), were the desired product 4 [(ethoxy)phenylmethyleneamino] 2,2,5,5- tetrakis (trifluoromethyl)-3--imidazoline; this material solidified on standing, M.P. 37-42 C. The H N.M.R. spectrum showed aromatic H centered at 1- 2.3, NH at 1- 3.67, a OCH C quartet (J=7) at 1- 5.45, and a OCH CH triplet (1:7) at '7' 8.54. The F N.M.R. spectrum showed a pair of septets (J=5) at +4094 and +4350 c.p.s. (external FCCl at 56.4 mc.).

Analysis.Calcd. for C H N F O (489.27) (percent): C, 39.28; H, 2.26; N, 8.59; F, 46.6. Found (percent): C, 39.03; H, 2.43; N, 8.54; F, 46.58.

EXAMPLE VI NCO CFa C 0-min- A 6-g. sample of 4-isocyanato-2,2,5,5-tetrakis(trifluoromethyl)-3-imidazoline (self-condensation product) and 10 g. of purified dimethylformamide (DM'F) were heated for 2 hours at reflux and the mixture was distilled through a spinning-band column. After the excess DMF was removed the product sublimed into the column. The solid in the pot was washed with pentane giving 2.26 g. of product, 4-[(dimethylamino) methyleneamino]-2,2,5,5- tetrakis(trifluoromethyl)-3-imidazoline. A sample for characterization was obtained by recrystallization from ether-pentane, M.P. 113-115 C. The procedure was repeated on a scale three times as large, except that the excess DMF was removed by distillation under reduced pressure and the residue vacuum sublimed, giving 16.15 g. (84%) of purified product. The H N.M.R. spectrum 15 (CCl D) showed a doublet (J=2.7) split further in doublets (1:0.6) centered at r 6.85 (area 6);

NH at T 6.5 and N=CHN at a- 1.5 The F N.M.R. spectrum showed a pair of septets (i=6) at +4064 and +4350 c.p.s. from external FCCl The mass spectrum showed the parent at m/e 412 and the expected fragmentation; the base peak was m/e 343 (parent -CF The ultraviolet spectrum showed igg 281 m,.(6=23,s00), Aim 280 m,t(e=22,700)

Analysis.Calcd. for C H N F (412.19) (percent): C, 29.13; H, 1.96; N, 13.60; F, 55.31. Found (percent): C, 29.50; H, 1.87; N, 14.28; F. 54.98.

On boiling for a few minutes with 3 N hydrochloric acid, this Schifi base regenerates the imidazoline.

EXAMPLE VII 4-[bis(dimethylamino)methyleneamino]-2,2,5,5- tetrakis (trifiuoromethyl) -3 -imidazoline A 6-g. sample of the isocyanate (self-condensation product of 4-isocyanato-2,2,5,S-tetrakis(trifluoromethyl)- 3-imidazoline) and 2.10 g. (one equiv.) of tetramethylthiourea were heated together at reflux for one hour. Sublimation gave 2.6 g. (36%) of product 4-[bis(dimethylamino)methyleneamino] 2,2,5,5 tetrakis(trifluoromethyD-S-imidazoline, M.P. 12ll29 C. The H N.M.R. spectrum showed NH at 1- 4.55 and 4 CH s at 1- 7.02. The F N.M.R. spectrum showed a pair of septets (J=) at +4087 and +4401 c.p.s. from external FCCl at 56.4 mc. The ultraviolet spectrum showed ACHiON 262 mm: 18,000)

max.

The mass spectrum showed a parent ion at m/e 455 and the expected fragmentation.

Analysis.Calcd. for C H N F (455.26) (percent): C, 31.65; H, 2.88; N, 15.38. Found (percent): C, 31.89; H, 2.92; N, 15.11.

EXAMPLE VIII 4- (benzylideneamino) -2,2,5 ,5 -tetrakis (trifluoromethyl S-imidazoline 1TI=CHC5H5 o A 5 .75-g. (0.015 mole) sample of 4-isocyanato-2,2,5,5- tetrakis(trifluoromethyl)-3-imidazoline was heated at reflux for 0.5 hour under a nitrogen atmosphere with g. of benzaldehyde (excess). The reaction mixture was distilled through a spinning-band column. The fractions boiling at 9598 C. (1.6 mm.) solidified on standing,

yielding 3.5 g. of 4-(benzylideneamino)-2,2,5,5-tetrakis- (trifiuoromethyl)-3-imidazoline. A scaled-up reaction using 30 g. of isocyanate and 50 g. of benzaldehyde gave 28 g. of benzylidene product, B.P. 91 C. mm.) The F N.M.R. spectrum showed a. pair of multiplets at +4103 and +4397 c.p.s. from FCCl at 56.4 mc. The H N.M.R. spectrum showed a multiplet in the arcmatic region and an NH band at 'r 3.6. The ultraviolet spectrum showed igggP 235 m,t e=5250), 24.5 m,. e=45s0),

273 m,t .=e05 280 m,. .=500

This compound is very easily hydrolyzed to a mixture of 4 amino-2,2,5,5,-tetrakis(trifluoromethyl) 3 imidazoline and benzaldehyde (minute amounts of benzoic acid present in the product catalyze this decomposition); it seems probable that the spectral properties reported above may be due to the hydrolysis mixture and not the benzylidene product. The infrared spectrum (Nujol) of the freshly prepared adduct is quite different from the one-toone mixture of 4-amino-2,2,5,5-tetrakis(trifluoromethyl)- 3-imidazoline and benzaldehyde. In addition, benzaldehyde may be removed from the mixture by washing with pentane, while the adduct is not decomposed by this treatment.

Analysis.-Calcd. for C H N F (445.22) (percent): C, 37.76; H, 1.59; N, 9.44; F, 51.2. Found (percent): C, 36.88; H, 1.64; N, 9.27; F, 51.45.

EXAMPLE IX 4- (dimethylamino) methyleneamino] -2-difluoromethy1- 2,5 ,5 -tris trifluoromethyl) -3-oxazoline A 3.1-g. sample of 4-isocyanato-2-(difluoromethyl)- 2,5,5-tris (trifluoromethyl)-3-oxaz0line was refluxed under a nitrogen atmosphere with 10 ml. of dry dimethylformamide (excess). The excess dimethylformamide was removed by distillation through a spinning-band column under reduced pressure. The residue was dissolved in ether and washed with water, dried over sodium sulfate and the ether exaporated. A white solid Schilf base, M.P. 44.545.5 C., 1.8 g. (57%), was obtained. The infrared spectrum showed no isocyanate bands and was consistent with the assigned structure. The H N.M.R. spectrum showed absorptions at 'r 6.80, 6.85 for the methyl groups, a triplet at 'r 4.15 (J=54 c.p.s.) for the CF H group, and a singlet at 1- 1.49 for the group. The F N.M.R. spectrum showed a doublet (split further) at +7445 c.p.s. (J=54 c.p.s.) for the CF H group, a multiplet at +4133 c.p.s. for the C(CF group and a triplet (i=9 c.p.s.) at 4366 c.p.s. for the group (internal ECCl at 54.6 mc.). The ultraviolet spectrum showed )\max 283 mu (e=24,200).

17 Analysis.-Calcd. for c mF' m-o (395.18) (percent): C, 30.39; H, 2.04; N, 10.63; F, 52.9. Found (percent): C, 30.00; H, 2.92; N, 10.70; F, 52.58.

The examples have illustrated the products of this invention by reference to specific compounds. However, the invention includes all compounds having the general Formula I. Other specific Schiif bases of Famine-2,25,5-

TABLE III Reactants Carbonyl or thiocarbonyl Isocyanate compound compound Product Ssehifi bases NCO N= 2 (CF3)2O N 0=CH2 (CF3)2C N EN(IJOF HN- --OF CFzH F211 H NCO 17 am: 0F3\ /H CF3\ /C\ 0=C /C HCF: I L 04H HCF: I

HN- -CF HN --OF3 CF H F 11 NCO =0 l CH; C aH40CHa 110F910 N =0 (HCFm N C H4OCH HN- (CFzH): HN-- (CFQH)! /IE[ 11100 =O\ OF; C H CF; (3 2-C1GH7 /0 =0 /0 N CICFQ I L u-CioH7 CICF: I

(CF92 HN-C(CF NCO (0101mm \N cmmmcmbm TABLE TIL-Continued Reactants Carbonyl or thiocarbonyl Isocyanate compound compound Products Schitf bases NC O N=O Ii HOFQ C 02:55 N(C H HGF, (J N(C H I 1 CF; O-CCF:H CF3 OCCF2H CHzCsH5 i u i o ouzrfiomomonm o ons), (HCFzh-C N (HCFQ N 0-C(CF2H)2 O -(CFzHh N 0 o 4 s)2]2 I =C[ o 4 a) 2]: CF; OF; 0

I l I I CICF: O--C(CF3)2 CICF: O-C(CF CaH5 NCO lS 1|\T=C (15115-6 O C4119 C 0 04119 2)2 N 02? N O-- (CFZCDQ Of(CFzCI);

The compounds of this invention, both the imidazoline and oxazoline Schiff bases, are useful for modifying polymers. They are especially effective in lowering the forming temperature or pressure of polymers. This is illustrated by the following experiments:

A sample of poly(methyl methacrylate) was melt pressed at 150 0, 7,000 p.s.i. for one minute. This gave a film of 9.5 mils thickness. A like amount of a mixture of 9 parts of this polymer and one part of 4- [p-(dimethylamino)phenylmethyleneamino] 2,2,5,5 tetrakis (trifluorornethyl)-3-imidazoline (the product of Example III) gave an orange-colored film of 3.25 mils thickness under the same pressing conditions. Pressing the above mixture at 135 C. and 7,000 p.s.i. for one minute, gave an orange-colored film of 5.5 mils thickness.

This also illustratesthe usefulness of the colored Schiff bases of this invention as dyes.

The compounds of this invention are also useful as waterand oil-repellent coatings for cellulosic materials. This is illustrated by the following experiments: Samples of 4-[ (dimethylamino)methyleneamino] -2,2,5,5-tetrakis(trifluoromethyl)-3-imidazoline and 4[(p-dimethylarninophenyl)methyleneamino] 2,2,5,5 tetrakis(trifluoromethyl)-3-imidazoline were dissolved in acetone and poured onto strips of filter paper. After drying, the treated strips were found to be yellow-colored and waterand oil-repellent while untreated strips of the paper were 'wetted by oil and water immediately.

The utility of compounds of this invention in therapeutical applications is demonstrated by the effectiveness of the compounds as muscle relaxants.

The muscle relaxant properties of the compounds of this invention were demonstracted by use of the Inclined Screen Test of L. O. Randall et al. [J. Pharm. Exp. Therap., 129, 163 (1960)]. By this test, is determined the oral doses which causes 50% of the test animals (mice) to lose their footing on a wire mesh which is inclined 30 from the horizontal. This dosage is called the paralyzing doses or PD value. In this test, low PD values indicate high potencies. 4-[(dimethylamino)methlyeneamino] 2,2,5,5-tetrakis(trifluoromethyl) 3 imidazoline has a PD value of 27 mg./ kg. with a standard error of :3.9 mg./ kg.

Another method for demonstrating muscle relaxant activity is the Wire Lift Test wherein the forefeet of albino mice are placed on a taut wire stretched at a level of approximately 12" over a fiat surface. Normal animals grasp the wire and lift the hind feet to the wire, Where balance is maintained. Inability to lift the hind legs to the wire is taken as a positive response and is considered to be a measure of muscle relaxation. Dose response relationships are determined by the method of L. C. Miller and M. L. Tainter, Proc. Soc. Exp. Biol. Med., 57, 261- 264 (1944).

The following Table IV gives effective doses or ED values for three compounds of this invention. Low ED values indicate high potencies.

TABLE IV.WIRE LIFT TEST FOR MUSCLE-RELAXANT ACTIVITY E ao Name of Compound istd EIl OI' 4-[(dimethylamino)methyleneamino1-2, 2, 5, 5-tetrakis (trifiuorornethyl) -3-imidazoline l3. 3:};1. 2 4-benzylidenearnino)-2, 2, 4, 5-tetrekis (trifluoro methyl) -3imidazoline 16=|= l. 4 4-[4-(dimethylamino)benzylideneamino1-2, 2, 5, 5-

tetrakis(trifluoromethyl)-3-imidazoline 375:5. G

The foregoing has been given for clarity of understanding only and no unnecessary limitations are to be understood therefrom. The invention is not limited to the exact details shown and described, for obvious modifications will be apparent to those skilled in the art.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A Schiff base of the formula 21 alkoxy, dialkylamino, dialkylaminophenyl, dialkylaminonaphthyl, alkoxyphenyl, and alkoxynaphthyl; and R is selected from R and a monovalent radical containing at most 18 carbons selected from alkyl, phenyl, naphthyl, alkylphenyl, alkylnaphthyl, phenylalkyl, and naphthylalky; (B) Z, Z Z and Z can be the same or different and are selected from hydrogen, chlorine and fluorine. 2. The Schifi base of claim 1, wherein Z, Z Z and Z are fluorine, R is dimethylamino and R is methyl; said 10 Schiff base being 4-[(dimethylamino)methylmethyleneamino] 2,2,5,5 tetrakis(trifiuoromethyl) 3 imidazoline.

3. The Schiff base of claim 1 wherein Z, Z Z and Z are fluorine, R is p-dimethylaminophenyl and R is hydrogen, said Schiff base being 4-[p-(dirnethylamino)- phenylmethyleneamino] 2,2,5,5 tetrakis (trifluoromethyl)-3-imidazoline.

22 4. The Schifi base of claim 1 wherein Z, Z Z and Z are fluorine, R is hydrogen and R is phenyl, said Schifi base being 4-(benzylideneamino)-2,2,5,5-tetrakis(trifiuoromethyl)-3-imidazo1ine.

5 References Cited UNITED STATES PATENTS 2,915,376 12/1959 Raifsnider 260-3096 3,326,976 6/1967 Middleton.

OTHER REFERENCES Layer: Chem. Rev., vol. 63, p. 496 relied on (1963). Staudinger et a1.: Berichte, v01. 50, pp. 1042-46 (1917).

15 NATALIE TROUSOF, Primary Examiner U.S. Cl. X.R. 424272, 273 

